Neonatal Exposure to Anesthesia Leads to Cognitive Deficits in Old Age: Prevention with Intranasal Administration of Insulin in Mice

Abstract

Recent pre-clinical and clinical studies suggest that general anesthesia in infants and children may increase the risk of learning disabilities. Currently, there is no treatment for preventing anesthesia-induced neurotoxicity and potential long-term functional impairment. Animal studies have shown that neonatal exposure to anesthesia can induce acute neurotoxicity and long-term behavioral changes that can be detected a few months later. It is currently unknown whether neonatal exposure, especially repeated exposures, to general anesthesia can induce or increase the risk for cognitive impairment during aging. Here, we report that repeated exposures of neonatal mice (P7–9 days old) to anesthesia with sevoflurane (3 h/day for 3 days) led to cognitive impairment that was detectable at the age of 18–19 months, as assessed by using novel object recognition, Morris water maze, and fear conditioning tests. The repeated neonatal exposures to anesthesia did not result in detectable alterations in neurobehavioral development, in tau phosphorylation, or in the levels of synaptic proteins in the aged mouse brains. Importantly, we found that treatment with intranasal insulin prior to anesthesia exposure can prevent mice from anesthesia-induced cognitive impairment. These results suggest that neonatal exposure to general anesthesia could increase the risk for cognitive impairment during aging. This study also supports pre-treatment with intranasal administration of insulin to be a simple, effective approach to prevent infants and children from the increased risk for age-related cognitive impairment induced by neonatal exposure to general anesthesia.

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Data Availability

The original data are available upon request to the investigators.

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Acknowledgments

We thank Jeffrey Goodman, PhD, and Maureen Marlow of the New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA, for the use of gas anesthesia equipment and for editing of the manuscript, respectively.

Funding

This work was supported in part by the New York State Office for People with Developmental Disabilities, Albany, NY, and a scholarship (to H.L.) from Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China.

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C-lD, C-XG, FL, and KI: designed research; C-lD, HL, XH, and JZ: performed research; C-lD, HL, XH, JZ, and C-XG: analyzed data; C-lD and C-XG: wrote the paper.

Corresponding author

Correspondence to Cheng-Xin Gong.

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Conflict of Interest

K.I. serves on the scientific advisory board of AXON Neuroscience, has received research grants from Ever NeuroPharma and Signum Biosciences, and holds several patents on treatment of Alzheimer’s disease and related conditions. C.-X.G. serves on the scientific advisory board of Alectos Therapeutics. K.I., F.L., and C.-X.G hold a patent on intranasal insulin administration for the minimization of anesthesia-induced memory loss.

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The housing, breeding, and animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the New York State Institute for Basic Research in Developmental Disabilities and were in accordance with the PHS Policy on Human Care and Use of Laboratory animals (revised March 15, 2010).

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Dai, C., Li, H., Hu, X. et al. Neonatal Exposure to Anesthesia Leads to Cognitive Deficits in Old Age: Prevention with Intranasal Administration of Insulin in Mice. Neurotox Res 38, 299–311 (2020). https://doi.org/10.1007/s12640-020-00223-y

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Keywords

  • Developing brain
  • Anesthesia
  • Sevoflurane
  • Insulin
  • Neuroprotection
  • Aging